Mechanisms of RNA virus-host interaction

RNA病毒与宿主相互作用的机制

• 批准号: 7393300
• 负责人: SAILEN BARIK
• 金额: $ 23.77万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393300
• 关键词: Accounting; Actins; Animal Model; Antiviral Agents; Area; Asthma; Binding; Biochemistry; Cells; Cellular Structures; Child; Complement; Complex; Cytoskeletal Proteins; Cytoskeleton; Disease; Gene Expression; Genetic Transcription; Goals; Growth and Development function; Hospitalization; Human; Human respiratory syncytial virus; In Vitro; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; Life; Light; Lung; Lung diseases; Maps; Modeling; Molecular; Morphogenesis; Mouse Strains; Mutate; Organelles; Pathway interactions; Phenotype; Phosphoproteins; Play; Proteins; RNA Interference; RNA Viruses; Recombinants; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Severe Acute Respiratory Syndrome; Signal Transduction; Structure; System; Treatment Protocols; Vaccines; Viral; Viral Proteins; Virus; Virus Diseases; ZYX gene; antitermination factor; base; cost; genetic regulatory protein; immunopathology; in vivo; influenza epidemic; insight; novel strategies; pathogen; peptidomimetics; profilin; reconstitution; transcription factor; vasodilator-stimulated phosphoprotein; viral RNA; virus host interaction

DESCRIPTION (provided by applicant): RNA viruses, in general, are deadly human pathogens, and highly efficient in evading antivirals and vaccines, due in part to their ability to mutate rapidly. The annual Flu epidemics and the recent emergence of SARS are important reminders. The long-term goal of this project is to understand the major areas of host-virus interaction in the gene expression and signal transduction of negative-strand RNA viruses, using primarily the human respiratory syncytial virus (RSV) as a model. RSV is a severe lung pathogen in children, causing respiratory diseases and asthma, and claiming nearly a million lives globally each year. In the US alone, RSV infection leads to about 100,000 hospitalizations, costing roughly $350 million to the US taxpayers. The immunopathology of RSV also is highly complex, making it difficult to formulate a reliable vaccine or antiviral. We reasoned that a prudent approach to the management of RSV should take into account the host-virus interactive pathways. In the last few years, we have shown that cellular actin is an essential transcription factor for RSV. Our recent studies using phenotypic knockdown of cellular proteins by a relatively novel strategy, known as "RNA interference", have revealed an essential role of 3 cytoskeletal-regulatory proteins (CRPs) in RSV maturation. These proteins are: profilin, VASP, and zyxin. Previous studies demonstrated that these proteins were relatively non-essential for the host cell. Thus, we propose that these CRPs could be potential targets for an antiviral regimen. Moreover, an understanding of their role in RSV morphogenesis would shed light on the fundamental mechanism of how the cytoskeleton may play a critical role in RNA viral maturation. Thus, the Specific Aims of the proposal involve detailed studies of: (i) the role of actin as a viral transcription factor; and (ii) the involvement of the CRPs in viral morphogenesis. The available CRP knockout mice strains will be used to complement and extend these studies to an animal model. Together, these results should lead to a better understanding of the replication of RSV in particular and of RNA viruses in general, and pave the way for a more reliable management of the viral diseases.

描述（由申请人提供）：通常，RNA病毒是致命的人类病原体，并且在逃避抗病毒药和疫苗方面高效，部分原因是它们迅速突变。年度流行流行病和SARS最近出现是重要的提醒。该项目的长期目标是将基因表达中的宿主病毒相互作用的主要领域和负链RNA病毒的信号转导，主要是使用人类呼吸道合胞病毒（RSV）作为模型。 RSV是儿童的严重肺病原体，导致呼吸道疾病和哮喘，每年在全球享有近一百万人的生命。仅在美国，RSV感染就会导致大约100,000次住院治疗，给美国纳税人耗资约3.5亿美元。 RSV的免疫病理学也很复杂，因此很难制定可靠的疫苗或抗病毒。我们认为，RSV管理的审慎方法应考虑到主机病毒交互式途径。在过去的几年中，我们表明细胞肌动蛋白是RSV的必不可少的转录因子。我们最近通过一种被称为“ RNA干扰”的相对新策略对细胞蛋白进行表型敲低的研究表明，3个细胞骨架调节蛋白（CRP）在RSV成熟中起着至关重要的作用。这些蛋白质是：profilin，vasp和zyxin。先前的研究表明，对于宿主细胞，这些蛋白质相对不必要。因此，我们建议这些CRP可能是抗病毒方案的潜在靶标。此外，了解它们在RSV形态发生中的作用将阐明细胞骨架如何在RNA病毒成熟中起关键作用的基本机制。因此，该提案的具体目的涉及：（i）肌动蛋白作为病毒转录因子的作用； （ii）CRP参与病毒形态发生。可用的CRP敲除小鼠菌株将用于补充和将这些研究扩展到动物模型。总之，这些结果应该可以更好地理解RSV的复制，尤其是对RNA病毒的复制，并为对病毒疾病的更可靠管理铺平道路。